Substituted hydrochromenopyrroles

ABSTRACT

Compounds of formula (I):                    
     wherein: 
     m is 0 to 3 inclusive, 
     n is 0 to 3 and 2≦m+n≦3, 
     p is 1 to 6 inclusive, 
     X represents cyano or —CO—NR 4 R 5 , R 4  and R 5  being selected from hydrogen, linear or branched (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, and aryl, 
     R 1  and R 2  each independently represent hydrogen or linear or branched (C 1 -C 6 )-alkyl, 
     R 3  represents hydrogen, optionally substituted phenyl, naphthyl or heteroaryl, or aryloxy or arylthio, or aryl or heteroaryl substituted by A′-Cy, A′ and Cy being as defined in the description, and 
     medicinal products containing the same which are useful as D 3  receptor ligands.

The present application is a division of our prior-filed applicationSer. No. 09/103,304, filed Jun. 23, 1998, now U.S. Pat. No. 6,090,837.

The present invention relates to new chromene compounds.

Apart from the fact that the compounds of the present invention are new,they have particularly valuable properties, binding selectively to D₃receptors compared with D₂ receptors.

BACKGROUND OF THE INVENTION

The discovery of those D₃ dopaminergic receptors (P. Sokoloff et al.,Nature, 1990, 347, 147), their strong concentration in the limbic systemand their low density in lactotrophic cells and in the nigrostriatedsystem, makes them a choice target for obtaining antipsychotics that donot have effects on the secretion of prolactin and are less liable tocause extrapyramidal-type syndromes. It has, in fact, been establishedthat the dopaminergic pathways extending to the limbic system and thecortex play a decisive role in the control of mood and in the aetiologyand treatment of psychiatric Aid disorders such as schizophrenia,depression, anxiety, aggression and other impulsive disorders (M. J.Milian et al., Drug News & Perspectives, 1992, 5, 397-406; A. Y. Deutchet al., Schizophrenia, 1991, 4, 121-156; H. Y. Meltzen et al.,Pharmacol. Rev., 1991, 43, 587-604).

DESCRIPTION OF THE PRIOR ART

The compounds of the prior art closest to those forming the subject ofthis Application were described for their dopaminergic or serotoninergicproperties (EP 691342; J. Med. Chem., 1989, 32, 720-7).

The compounds of the present application are characterised by thepresence of carboxamide or nitrile-type electron-attracting substituentswhich, surprisingly, allow enhancement of the D₃ dopaminergic propertiesin terms of strength and selectivity. The selectivity makes the productsof the invention especially valuable for use as medicaments acting onthe dopaminergic system that do not have the undesirable effects of D₂ligands. In the light of results that have appeared in the literature,it is possible for them to be used in the treatment of impulsivedisorders (for example those caused by drug abuse, B. Caine, Science,1993, 260, 1814), aggressiveness (J. W. Tidey, Behavioral Pharm., 1992,3, 553), Parkinson's disease (J. Carlson, Neur. Transm., 1993, 94, 11),psychoses, memory disorders (P. Sokoloff et al., Nature, 1990, 347,147), anxiety and depression (P. Willner, Clinical Neuropharm., 1985,18, suppl. 1, 549-56).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates more specifically to compounds of formula(I):

wherein:

m is an integer such that 0≦m≦3,

n is an integer such that 0≦n≦3 and 2≦m+n≦3,

p is an integer such that 1≦p≦6,

the junction between the B and C rings is in the trans configuration,

X represents a cyano group or a group —CO—NR₄R₅, R₄ and R₅ beingselected from hydrogen, linear or branched (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and optionally substituted aryl,

A represents a σ bond or a group selected from —NR—CO—, —CO—NR—, —NR—SO₂and —SO₂—NR wherein R represents a hydrogen atom or a linear or branched(C₁-C₆)-alkyl group,

R₁ and R₂ each independently represent a hydrogen atom or a linear orbranched (C₁-C₆)-alkyl group,

R₃ represents:

a hydrogen atom, or a phenyl, naphthyl or heteroaryl group each of whichis optionally substituted by one or more halogen atoms, linear orbranched (C₁-C₆)-alkyl, linear or branched (C₁-C₆)-alkoxy, hydroxy,cyano, amino, nitro, carboxy, linear or branched (C₁-C₆)-perhaloalkyl,sulpho, acylamino, linear or branched (C₁-C₆)-alkylsulphonyl or linearor branched (C₁-C₆)-alkylsulphonylamino groups,

an aryl or heteroaryl group substituted by a group A′-Cy wherein A′represents a σ bond, a linear or branched (C₁-C₆)-alkylene group (inwhich a carbon atom may optionally be replaced by an oxygen or sulphuratom), a linear or branched (C₁-C₆)-alkenylene group (in which a carbonatom may optionally be replaced by an oxygen or sulphur atom) or a group—NR—CO—, —CO—NR, —NR—SO₂— or SO₂—NR (in which R represents a hydrogenatom or a linear or branched (C₁-C₆)-alkyl group), and Cy represents anoptionally substituted aryl group or an optionally substitutedheteroaryl group,

a 2-indolinon-5-yl group,

or an aryloxy or arylthio group (with the proviso that in that case Arepresents a σ bond),

 provided that:

when n is 0, m is other than 2,

when n is 1, R₁ and R₂ represent a hydrogen atom, A represents a σ bondand p is 1, R₃ is other than phenyl or pyridyl,

when n is 1, R₁ and R₂ represent a hydrogen atom and A represents a σbond, R₃ is other than a hydrogen atom,

when n is 1, R₁ and R₂ represent a hydrogen atom and A represents an—NH—CO—group, R₃ is other than a hydrogen atom or a phenyl, naphthyl, orheterocyclic group selected from thienyl, furyl, pyrrolyl and pyridyl,each of those groups being optionally substituted by one or more halogenatoms or trihalomethyl, alkoxy or hydroxy groups,

their isomers, enantiomers and diastereoisomers, and also the additionsalts thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned byway of non-limiting example hydrochloric, hydrobromic, sulphuric,acetic, trifluoroacetic, lactic, malonic, succinic, glutamic, fumaric,maleic, citric, oxalic, methanesulphonic, benzenesulphonic and camphoricacid etc.

Among the pharmaceutically acceptable bases there may be mentioned byway of non-limiting example sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine etc.

An aryl group is to be understood as meaning a phenyl or naphthyl group.

A heteroaryl group is to be understood as meaning a mono- or bi-cyclicaromatic group containing from 5 to 13 chain members and from one tofour hetero atoms selected from nitrogen, oxygen and sulphur, forexample a furyl, pyridyl or thienyl group.

The expression “optionally substituted” describing aryl and heteroarylsignifies that those groups are optionally substituted by one or morehalogen atoms or linear or branched (C₁-C₆)-alkyl, hydroxy, linear orbranched (C₁-C₆)-alkoxy, linear or branched (C₁-C₆)-perhaloalkyl, cyano,nitro, sulfo, amino, linear or branched (C₁-C₆)-acyl, acylamino, linearor branched (C₁-C₆)-alkylsulfonyl or linear or branched(C₁-C₆)-alkylsulpholamino groups.

The term “acyl”, alone or in the expression “acylamino”, represents alinear or branched (C₁-C₆)-alkylcarbonyl group or a(C₃-C₈)-cycloalkylcarbonyl group.

Preferably, the invention relates to compounds of formula (I) wherein mand n are each 1.

Other preferred compounds of the invention are those wherein m is 3while n is 0.

In compounds of formula (I), X preferably represents a cyano group.

In preferred compounds of the invention, A represents a σ bond or anNR—CO— or NR—SO₂ group, R preferably being a hydrogen atom.

In compounds of formula (I), R₁ and R₂ each more especially represents ahydrogen atom.

Preferred R₃ groups of the invention are optionally substituted phenylor optionally substituted biphenyl groups.

Another preferred group R₃ is an aryl group (more especially phenyl)substituted by a group A′-Cy wherein A′ preferably represents an NR—COor NR—SO₂ group (R being more especially a hydrogen atom) and Cypreferably represents an optionally substituted aryl group.

Another preferred R₃ group is the group 2-indolinon-5-yl.

The invention relates more preferably to compounds of formula (I)wherein X represents a cyano group, m and n are each 1, R₁ and R₂ eachrepresent a hydrogen atom, and p is 4 when A represents an NHCO groupand R₃ represents an optionally substituted phenyl group or anoptionally substituted biphenyl group, or p is 1 or 2 when A representsa σ bond and R₃ represents an optionally substituted phenyl group or anoptionally substituted biphenyl group.

The invention extends also to a process for the preparation of compoundsof formula (I) which is characterised in that there is used as startingmaterial a compound of formula (II):

wherein X, m and n are as defined for formula (I),

which is treated

with a compound of formula (III):

 wherein G represents a halogen atom or a CHO group, q is an integersuch that 0≦q≦6, and R₁, R₂ and R₃ are as defined for formula (I),

to yield, after reduction when G represents a CHO group, a compound offormula (I/a):

a particular case of compounds of formula (I) wherein X, R₁, R₂, R₃, m,n and p are as defined for formula (I),

or with a compound of formula (IV):

 wherein Y represents a halogen atom, R, R₁, R₂, R₃ and p are as definedfor formula (I) and T represents a CO or SO₂ group,

to yield a compound of formula (I/b):

 a particular case of compounds of formula (I) wherein X, R, R₁, R₂, R₃,m, n and p are as defined for formula (I) and T is as defined above,

or with a compound of formula (V):

 wherein Y represents a halogen atom, R, R₁, R₂, R₃ and p are as definedfor formula (I) and T represents a CO or SO₂ group,

to yield a compound of formula (I/c):

 a particular case of compounds of formula (I) wherein X, R, R₁, R₂, R₃,m, n and p are as defined for formula (I) and T is as defined above,

or with a compound of formula (III′):

 wherein G represents a halogen atom or a CHO group, p, R₁ and R₂ are asdefined for formula (I) and R₃₁ represents an aryl or heteroaryl groupsubstituted by a halogen atom or by a carboxy, nitro or sulpho group,

to yield a compound of formula (I′/a):

 a particular case of compounds of formula (I/a) wherein X, R₁, R₂, R₃₁,m, n and p are as defined hereinbefore,

 which:

when R₃₁ represents an aryl or heteroaryl group substituted by a halogenatom, is treated with an appropriate vinyl compound, tin compound orboronic acid compound in the presence of a palladium catalyst

to yield a compound of formula (I/d):

 a particular case of compounds of formula (I) wherein X, R₁, R₂, R₃₁,m, n and p are as defined hereinbefore, R′₃ represents an aryl orheteroaryl group, A′₁ represents a σ bond, an alkylene group (in which acarbon atom may optionally be replaced by an oxygen or sulphur atom) oran alkenylene group (in which a carbon atom may optionally be replacedby an oxygen or sulphur atom) and Cy is as defined for formula (I),

when R₃₁ represents an aryl or heteroaryl group substituted by a nitrogroup, after reduction of that group to amine, is treated with acompound of formula Cl—CO—Cy or Cl—SO₂—Cy to yield a compound of formula(I/e):

 a particular case of compounds of formula (I) wherein X, R₁, R₂, m, n,p and Cy are as defined for formula (I), R′₃ represents an aryl orheteroaryl group and A′₂ represents an —NR—CO or —NR—SO₂— group (R beingas defined for formula (I)),

when R₃₁ represents an aryl or heteroaryl group substituted by a sulphoor carboxy group, is treated with a compound of formula HNR—Cy to yielda compound of formula (I/f):

 a particular case of compounds of formula (I) wherein X, R₁, R₂, m, n,p and Cy are as defined for formula (I), R′₃ represents an aryl orheteroaryl group and A′₃ represents a —CO—NR— or —SO₂—NR— group (R beingas defined hereinbefore),

which compounds of formulae (I/a) to (I/f):

are purified, if necessary, according to a conventional purificationtechnique,

are separated, where appropriate, into the enantiomers according to aconventional separation technique,

are converted, if desired, into addition salts with a pharmaceuticallyacceptable acid or base,

with the proviso that when X represents a CN group it may be convertedinto an aminoalkyl group according to conventional techniques of organicchemistry at any stage of the synthesis.

With the aim of providing a synthesis better adapted to certain productsof formula (I) it is desired to obtain, it shall be possible for certainvariants of the above-described process to be used.

One such variant comprises using as starting material a compound offormula (VI):

wherein m and n are as defined for formula (I) and R₆ represents alinear or branched (C₁-C₆)-alkyl group,

which is treated with trifluoromethanesulphonic anhydride to yield acompound of formula (VII):

wherein R₆, m and n are as defined hereinbefore,

which compound of formula (VII) reacts with tributyltin cyanide in thepresence of lithium chloride and a palladium(O) catalyst to yield acompound of formula (I/g):

a particular case of compounds of formula (I) wherein R₆, m and n are asdefined hereinbefore,

which compound of formula (I/g) may, if necessary, be purified byconventional purification methods and may, where appropriate, beseparated into the enantiomers by a conventional separation techniqueand may, if desired, be converted into an addition salt with apharmaceutically acceptable acid or base.

The present invention relates also to the use, for the manufacture ofpharmaceutical compositions for use in the treatment of disordersrequiring a D₃ receptor ligand, of compounds of formula (VIII):

wherein:

represents 1 or 2,

Z represents a cyano or aminocarbonyl group,

R₇ represents a linear or branched (C₁-C₆)-alkyl group, a benzyl groupor an acylamino-(C₁-C₆)-alkyl group (in which the alkyl moiety is linearor branched and in which the acyl group is a benzoyl, naphthylcarbonyl,thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl or pyridinylcarbonylgroup each of which is optionally substituted by one or more halogenatoms or trihalomethyl, alkoxy or hydroxy groups),

the junction between the rings B and C is in the trans configuration,compounds (VIII) being described in the application EP 691 342.

The invention extends also to pharmaceutical compositions comprising asactive ingredient at least one compound of formula (I), alone or incombination with one or more inert, non-toxic excipients or carriers.

Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those which are suitable for oral,parenteral or nasal administration, tablets or dragees, sublingualtablets, gelatin capsules, lozenges, suppositories, creams, ointments,dermal gels etc.

The useful dosage varies according to the age and weight of the patient,the nature and severity of the disorder and the administration route,which may be nasal, rectal, parenteral or oral. Generally, the unit doseranges from 1 to 500 mg for a treatment of from 1 to 3 administrationsper 24 hours.

The Examples which follow illustrate the invention and do not limit itin any way. The structures of the described compounds were confirmed bycustomary spectroscopic techniques.

The Preparations described below lead to the starting materials used inthe synthesis of the compounds of the invention.

PREPARATION A 3-Nitrophenylacetaldehyde

90 mmol of iodoxybenzoic acid are added to 60 mmol of2-(3-nitrophenyl)ethanol in 300 ml of tetrahydrofuran. The reactionmixture is heated at reflux for 4 hours, then cooled and filtered. Thefiltrate is concentrated to yield the expected compound.

PREPARATION B N-[4-(2-Chloroethyl)phenyl]acetamide

Step a: N-(4-Chloroacetylphenyl)acetamide

23.5 mmol of chloroacetyl chloride and, in portions, 18.1 mmol ofacetanilide, are added slowly, under an argon atmosphere, to 108 mmol ofaluminium chloride in 90 ml of 1,2-dichloroethane. The reaction mixtureis heated at 60° C. for 2 hours and then cooled with an ice bath. Afterslow hydrolysis using ice, and filtration, the precipitate obtained iswashed with ethyl ether and dried. The expected product so obtained isused in the following without being purified.

Step b: N-[4-(2-Chloroethyl)phenyl]acetamide

22.7 mmol of triethylsilane are slowly added to 11.1 mmol of the productobtained in the above Step dissolved in 10 ml of trifluoroacetic acid.Stirring is maintained for 24 hours. The trifluoroacetic acid is thenremoved and the residue obtained is taken up in 50 ml of acetonitrileand then washed with hexane (4 times 30 ml). After concentration, theexpected product is purified by chromatography on silica gel using a90/10 dichloromethane/ethyl acetate mixture as eluant.

PREPARATION C 5-(2-Chloroethyl)-1,3-dihydro-2-oxo-indole

Step a: 5-Chloroacetyl-1,3-dihydro-2-oxo-indole

The expected product is obtained in accordance with the processdescribed in Preparation B, Step a, replacing the acetanilide with1,3-dihydro-2-oxo-indole.

Step b: 5-(2-Chloroethyl)-1,3-dihydro-2-oxo-indole

The expected product is obtained in accordance with the processdescribed in Preparation B, Step b, starting from the compound obtainedin the above Step.

PREPARATION D 4-Cyano-N-(4-hydroxybutyl)benzamide

100 mmol (9.2 ml) of 4-aminobutanol are slowly added, at a temperatureof 5° C., to 100 mmol (16.56 g) of 4-cyanobenzoyl chloride in 400 ml ofdichloromethane. While maintaining the temperature at 5° C., 100 mmol(13.9 ml) of triethylamine are added. The reaction mixture is stirredfor 15 hours at room temperature before being hydrolysed. The organicphase is then decanted off and washed with a 1N hydrochloric acidsolution. After evaporating off the solvent, the residue obtained ispurified by chromatography on silica gel using a 97/3dichloromethane/methanol mixture as eluant to yield the expectedproduct.

PREPARATION E 4-Phenyl-N-(4-hydroxybutyl)benzamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride with4-phenylbenzoyl chloride.

PREPARATION F 4-Bromo-N-(4-hydroxybutyl)benzamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride with4-bromobenzoyl chloride.

PREPARATION G 4-Fluoro-N-(4-hydroxybutyl)benzamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride with4-fluorobenzoyl chloride.

PREPARATION H N-(4-Hydroxybutyl)-2-trifluoromethylbenzamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride with2-trifluoromethylbenzoyl chloride.

PREPARATION I N-(4-Bromophenyl)-5-chloropentanamide

366 mmol (26.7 ml) of thionyl chloride are added dropwise to 183 mmol(25 g) of 5-chlorovaleric acid in 250 ml of toluene heated at reflux.The mixture is stirred at reflux until the evolution of gas has ceasedand is then cooled. The solvent is evaporated off. The product obtainedis then redissolved in 250 ml of dichloromethane and the temperature islowered to 5° C. A solution of 183 mmol (31.5 g) of 4-bromoaniline in100 ml of dichloromethane and 183 mmol (25.5 ml) of triethylamine areadded in succession. The reaction mixture is stirred for 4 hours at 5°C. and then for 15 hours at room temperature. Hydrolysis, washing theorganic phase with a 1N hydrochloric acid solution and evaporating offthe solvents yields the expected product, which is used without beingpurified.

PREPARATION J 4-Phenylbenzaldehyde

65 mmol of 4-benzylpyridinium dichromate are added to 54 mmol of4-phenylbenzyl alcohol in 400 ml of dichloromethane. The reactionmixture is stirred for 2 hours at room temperature. 600 ml of a mixtureof ethyl ether and hexane in a ratio of 1 to 1 are added. After stirringfor 30 minutes, the mixture is filtered. The filtrate is washed oncewith 100 ml of a 1N hydrochloric acid solution. The organic phase isdried over magnesium sulphate and then concentrated to yield theexpected compound.

PREPARATION K 4-Biphenylacetaldehyde

The expected product is obtained in accordance with the processdescribed in Preparation A, replacing the 2-(3-nitrophenyl)ethanol with2-(4-biphenyl)ethanol.

PREPARATION L 4-Bromophenylacetaldehyde

The expected product is obtained in accordance with the processdescribed in Preparation A, replacing the 2-(3-nitrophenyl)ethanol with4-bromophenylethanol.

PREPARATION M 4-Nitrophenylacetaldehyde

The expected product is obtained in accordance with the processdescribed in Preparation A, replacing the 2-(3-nitrophenyl)ethanol with2-(4-nitrophenyl)ethanol.

PREPARATION N 4-Bromo-N-(4-hydroxybutyl)benzenesulphonamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride with4-bromobenzenesulphonyl chloride.

PREPARATION O 4-Fluoro-N-(4-hydroxypropyl)benzamide

The expected product is obtained in accordance with the processdescribed in Preparation G, replacing the 4-aminobutanol with3-aminopropanol.

PREPARATION P 4-Acetylbenzoyl chloride

120 mmol of thionyl chloride are added to 600 mmol of 4-acetylbenzoicacid in 150 ml of toluene. The reaction mixture is heated at reflux for3 hours and then cooled. The solvent is evaporated off. The product isused without any other treatment.

PREPARATION Q 4-Cyano-N-(4-hydroxybutyl)-1-methoxy-2-naphthylamide

Step a: Methyl 2-(1-hydroxy)naphthoate

500 mmol of O-methylcaprolactim are added to 500 mmol of1-hydroxy-2-naphthoic acid. The mixture is heated at 85° C. for 15 hoursand then cooled. After the addition of 50 ml of ethyl ether andadjustment of the pH to 9-10, the mixture is extracted with ethyl ether.The organic phases are combined and dried over magnesium sulphate. Theexpected product is precipitated from isopropyl ether and isolated byfiltration.

Step b: Methyl 2-(4-bromo-1-hydroxy)naphthoate

440 mmol of bromine are slowly added to 370 mmol of the compoundobtained in Step a. The mixture is stirred for 3 hours at roomtemperature before being diluted with water. The precipitate formed iswashed with water, filtered and dried to yield the expected product.

Step c: Methyl 2-(4-bromo-1-methoxy)naphthoate

350 mmol of the compound obtained in Step b are added to 530 mmol ofpotassium carbonate in 2 liters of acetone. 590 mmol of dimethylsulphate are then added. The reaction mixture is heated at reflux for 4hours and then filtered. The filtrate is concentrated. The residue istaken up in isopropyl ether and the precipitate formed is filtered toyield the expected compound.

Step d: Methyl 2-(4-cyano-1-methoxy)naphthoate

110 mmol of the compound obtained in the above Step, 70 mmol of zinccyanide and 7 mmol of tetrakis(triphenylphosphine)palladium are added to120 ml of dimethylformamide. The reaction mixture is heated at 80° C.for 5 hours and then cooled and diluted with dichloromethane. Theorganic phase is washed with a 2N ammonium hydroxide solution and thendried over magnesium sulphate. The expected product is obtained afterpurification by chromatography on silica gel.

Step e: 2-(4-Cyano-1-methoxy)naphthoic acid

32 mmol of the compound obtained in the above Step are dissolved in 80ml of water plus 80 ml of tetrahydrofuran. 36 mmol of lithium hydroxideare then added. After 2 hours the tetrahydrofuran is evaporated off. Theaqueous phase is washed with ethyl ether and then adjusted to pH 3. Theprecipitate obtained is filtered off and washed with water to neutralpH, and is then dried to yield the expected product.

Step f; 2-(4-Cyano-1-methoxy)naphthoic acid chloride

The expected product is obtained in accordance with the processdescribed in Preparation P, replacing the 4-acetylbenzoic acid with thecompound obtained in the above Step.

Step g: 4-Cyano-N-(4-hydroxybutyl)-1-methoxy-2-naphthylamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride withthe compound obtained in the above Step.

PREPARATION R 4-Fluoro-N-(2-hydroxyethyl)benzamide

The expected product is obtained in accordance with the processdescribed in Preparation G, replacing the 4-aminobutanol with2-aminoethanol.

PREPARATION S 4-Phenyl-N-(2-hydroxyethyl)benzamide

The expected product is obtained in accordance with the processdescribed in Preparation E, replacing the 4-aminobutanol with2-aminoethanol.

PREPARATION T 4-Methoxy-N-(4-hydroxybutyl)benzenesulphonamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride with4-methoxybenzenesulphonyl chloride.

PREPARATION U 4-Nitro-N-(4-hydroxybutyl)benzenesulphonamide

The expected product is obtained in accordance with the processdescribed in Preparation D, replacing the 4-cyanobenzoyl chloride with4-nitrobenzenesulphonyl chloride.

PREPARATION V 4-Bromo-N-(3-hydroxypropyl)benzenesulphonamide

The expected product is obtained in accordance with the processdescribed in Preparation N, replacing the 4-aminobutanol with3-aminopropanol.

PREPARATION W 4-Nitro-N-(3-hydroxypropyl)benzenesulphonamide

The expected product is obtained in accordance with the processdescribed in Preparation U, replacing the 4-aminobutanol with3-aminopropanol.

PREPARATION X 4-Bromo-N-(2-hydroxyethyl)benzenesulphonamide

The expected product is obtained in accordance with the processdescribed in Preparation N, replacing the 4-aminobutanol with2-aminoethanol.

PREPARATION Y 4-Methoxy-N-(2-hydroxyethyl)benzenesulphonamide

The expected product is obtained in accordance with the processdescribed in Preparation T, replacing the 4-aminobutanol with2-aminoethanol.

EXAMPLE 1(4aα,10bβ)-9-Cyano-4-propyl-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinehydrochloride

Step a:(4aα,10bβ)-9-hydroxy-4-propyl-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinemethanesulphonate

To 6.4 mmol of9-hydroxy-4-propyl-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b] pyridine(described in J. Med. Chem., 1989, 32, 720-7) dissolved in 100 ml ofdichloromethane and cooled to −30° C. there are added, in succession,9.7 mmol of 2,6-lutidine, 1.3 mmol of 4-dimethylaminopyrddine and 9.7mmol of triflic anhydride dropwise. After 30 minutes′ stirring, themixture is hydrolysed with a saturated NaCl solution. The organic phaseis then decanted off and subsequently concentrated, and the expectedproduct is purified by chromatography on silica gel.

Step b:(4aα,10bβ)-9-Cyano-4-propyl-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinehydrochloride

5.4 mmol of tributyltin cyanide, 7.8 mmol of lithium chloride and 2.6mmol of tetrakis(triphenylphosphine)palladium are added in succession to2.6 mmol of the compound prepared in the above Step in 20 ml of1,2-dichloroethane. The reaction his mixture is heated at reflux for 18hours. After cooling and hydrolysis with a saturated potassium fluoridesolution, the mixture is filtered. The organic phase is decanted off andconcentrated. The expected product is obtained by purification bychromatography on silica gel.

The corresponding hydrochloride is obtained by the action of a titratedsolution of hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 65.63 7.23 12.11 9.57 %found 65.28 7.06 11.77 9.30

EXAMPLE 2(3aα,9bβ)-8-Cyano-2-phenethyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

10 mmol of potassium carbonate are added to 5 mmol of(3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4c]pyrrole(described in application EP 691 342) in 50 ml of acetonitrile. Thereaction mixture is stirred at room temperature for 15 minutes. 0.5 mmolof potassium iodide and 5 mmol of phenethyl bromide dissolved in 50 mlof acetonitrile are added in succession. The reaction mixture is thenheated at reflux for 15 hours. After hydrolysis and extraction withdichloromethane, the organic phases are combined and concentrated. Theexpected product is obtained by purification by chromatography on silicagel using a 95/5 dichloromethane/methanol mixture as eluant. The productis converted into the corresponding hydrochloride using a solution ofethanol saturated with hydrochloric acid.

Elemental microanalysis: C H Cl N % calculated 70.48 6.21 10.40 8.22 %found 70.42 6.24 10.45 7.78

EXAMPLE 3(3aα,9bβ)-8-Cyano-2-[2-(3-methylsulphonylaminophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

Step a:(3aα,9bβ)-8-Cyano-2-[2-(3-nitrophenyl)ethyl]-1,2,3,3a,4,9b-hexahydro-chromeno[3,4-c]pyrrole

30 mmol of(3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole(described in application EP 691 342) and then 30 mmol of acetic acidare added to 60 mmol of the compound described in Preparation A in 500ml of 1,2-dichloroethane. After 10 minutes, 42 mmol of sodiumtriacetoxyborohydride are added. The reaction mixture is stirred at roomtemperature for 15 hours, then washed with a saturated sodium hydrogencarbonate solution. The organic phase is decanted off, dried andconcentrated. The expected product is obtained by purification bychromatography on silica gel using a 97/3 toluenelethanol mixture aseluant.

Step b:(3aα,9bβ)-8-Cyano-2-[2-(3-aminophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole

0.6 g of 10% palladium-on-carbon are added to 9 mmol of the compoundobtained in the above Step in 300 ml of ethanol. The reaction mixture isplaced under a hydrogen atmosphere for 1 hour 30 minutes. The expectedproduct is obtained after filtering off the catalyst and concentratingthe filtrate.

Step c:(3aα,9bβ)-8-Cyano-2-[2-(3-methylsulphonylaminophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

9 mmol of the compound obtained in Step b dissolved in dichloromethaneare added at −5° C. to 10 mmol of methanesulphonyl chloride in 15 ml ofdichloromethane. After 15 hours' stirring at room temperature, themixture is treated with 1N sodium hydroxide solution. The organic phaseis decanted off, dried and concentrated. The expected product isobtained by purification by chromatography on silica gel using a 95/5dichloromethane/methanol mixture as eluant. The correspondinghydrochloride is obtained by the action of a titrated solution ofhydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N S % calculated 58.12 5.57 8.17 9.687.39 % found 58.56 5.85 8.25 9.37 6.98

EXAMPLE 4(3aα,9bβ)-2-[2-(4-Acetylaminophenyl)ethyl]-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 2, replacing the phenethyl bromide with thecompound described in Preparation B.

Elemental microanalysis: C H Cl N % calculated 66.41 6.08 8.91 10.56 %found 66.35 6.10 8.89 10.25

EXAMPLE 5(3aα,9bβ)-8-Cyano-2-[2-(2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 2, replacing the phenethyl bromide with thecompound described in Preparation C.

Elemental microanalysis: C H Cl N % calculated 66.75 5.60 8.96 10.61 %found 66.24 5.77 8.51 10.45

EXAMPLE 6(3aα,9bβ)-2-(4-Bromobenzyl)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 2, replacing the phenethyl bromide with4-bromobenzyl bromide.

Elemental microanalysis: C H Cl N % calculated 56.25 4.47 8.74 6.90 %found 56.50 4.74 8.37 6.45

EXAMPLE 7(3aα,9bβ)-2-(4-Acetylaminobenzyl)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained using the process described in Example3, Step a, replacing the product of Preparation A with4-acetylaminobenzaldehyde.

EXAMPLE 8(3aα,9bβ)-8-Cyano-(4-fluorobenzyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained using the process described in Example3, Step a, replacing the product of Preparation A with4-fluorobenzaldehyde.

EXAMPLE 9(3aα,9bβ)-8-Cyano-(3-nitrobenzyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained using the process described in Example2, replacing the phenethyl bromide with 3-nitrobenzyl bromide.

EXAMPLE 10(3aα,9bβ)-2-Benzyl-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno-[3,4-c]pyrrolehydrochloride

The product is described in Example 29 of the application EP 691 342.

EXAMPLE 11(3aα,9bβ)-8-Aminocarbonyl-2-benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

40 g of polyphosphoric acid are added to 15 mmol of the compounddescribed in Example 10. The mixture is heated at 140° C. for 4 hoursand then poured into an ice bath. The pH is adjusted to 12 by theaddition of a concentrated aqueous NaOH solution. After the addition of1 liter of water and 300 ml of dichloromethane, the biphasic mixture isstirred for 15 hours and then decanted. After extraction, the organicphase is dried and concentrated. The expected product is obtained bypurification by chromatography on silica gel using a 96/4/0.4dichloromethane/methanol/ammonium hydroxide mixture as eluant. Thecorresponding hydrochloride is obtained by the action of a titratedsolution of hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 66.18 6.14 10.28 8.12 %found 65.64 6.16 10.01 7.84

EXAMPLE 12(3aα,9bβ)-8-Cyano-2-propyl-1,2,3,3a,4,9b-hexahydrochromeno-[3,4-c]pyrrolehydrochloride

The product is described in Example 31 of application EP 691 342.

EXAMPLE 134-Cyano-N-[4-((3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)butyl]benzamidehydrochloride

At −60° C., 20 mmol of dimethyl sulphoxide dissolved in 12 ml ofdichloromethane are added to 20 mmol of oxalyl chloride dissolved in 48ml of dichloromethane. A solution of the compound described inPreparation D in 32 ml of dichloromethane is slowly added. The reactionmixture is maintained at −60° C. for 45 minutes, then 50 mmol oftriethylamine are slowly added. The reaction mixture is allowed toreturn to room temperature. After hydrolysis and extraction withdichloromethane, the organic phase is washed with a saturated solutionof sodium chloride and concentrated. The product obtained is redissolvedin 50 ml of 1,2-dichloroethane and then 10 mmol of(3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole(described in application EP 691 342) and 10 mmol of acetic acid areadded in succession. After 10 minutes' stirring, 17.5 mmol of sodiumtriacetoxyborohydride are added. Stirring is maintained for 15 hours andthen the mixture is hydrolysed with a saturated solution of sodiumhydrogen carbonate. After extraction with dichloromethane, the expectedproduct is obtained by purification by chromatography on silica gelusing a 95/5 dichloromethane/methanol mixture as eluant. Thecorresponding hydrochloride is obtained by the action of a solution ofethanol saturated with hydrochloric acid.

Elemental microanalysis: C H Cl N % calculated 65.97 5.77 8.11 12.82 %found 66.67 5.79 8.16 12.73

EXAMPLE 14N-[4-((3aα,9bβ)-8-Cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)butyl]-4-phenylbenzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 7, replacing the product of Preparation D with thecompound described in Preparation E.

Elemental microanalysis: C H Cl N % calculated 71.37 6.20 7.26 5.61 %found 71.46 6.17 7.54 8.51

EXAMPLE 154-Bromo-N-[4-((3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)butyl]benzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation F.

Elemental microanalysis: C H Br Cl N % calculated 56.28 5.13 16.28 7.228.56 % found 56.10 5.03 16.00 7.17 8.49

EXAMPLE 16N-[4-((3aα,9bβ)-8-Cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)butyl]-4-fluorobenzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation G.

Elemental microanalysis: C H Cl N % calculated 64.26 5.86 8.25 9.77 %found 64.08 5.93 8.69 9.62

EXAMPLE 17N-[4-((3aα,9bβ)-8-Cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)butyl]-2-trifluoromethylbenzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation H.

Elemental microanalysis: C H Cl N % calculated 60.06 5.25 7.39 8.76 %found 60.47 5.15 7.36 8.87

EXAMPLE 18N-(4-Bromophenyl)-5-[(3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl]pentanamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 2, replacing the phenethyl bromide with thecompound described in Preparation I.

EXAMPLE 19(3aα,9bβ)-8-Aminocarbonyl-2-[2-(2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 11, replacing the compound of Example 10 with theproduct described in Example 5.

Elemental microanalysis: C H Cl N % calculated 63.52 5.92 8.60 9.98 %found 63.84 5.84 8.52 10.15

EXAMPLE 20(3aα,9bβ)-8-Cyano-2-(4-phenylbenzyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith that of Preparation J. The product is converted into thecorresponding hydrochloride using a titrated solution of hydrochloricacid in ethanol.

Elemental microanalysis: C H Cl N % calculated 74.62 5.86 8.61 6.85 %found 74.52 5.50 8.78 6.95

EXAMPLE 21(3aα,9bβ)-8-Cyano-2-[4-(4-fluorophenyl)benzyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

2.7 mmol of the compound of Example 6 in the form of its base, 2.7 ml ofa 2M solution of sodium carbonate and 3 mmol of 4-fluorophenylboronicacid dissolved in 2 ml of ethanol are added to 100 mg oftetrakis(triphenylphosphine)palladium in 20 ml of toluene. The reactionmixture is heated at reflux for 3 hours and then cooled. 0.2 ml of asolution of 30% hydrogen peroxide in water is added. After 30 minutes'stirring, 50 ml of ethyl ether are added. The mixture is decanted andthe aqueous phase is extracted once with ether. The organic phases arecombined and washed with a saturated solution of sodium chloride andthen dried over magnesium sulphate. The expected product is obtainedafter purification by chromatography on silica gel. The product isconverted into the corresponding hydrochloride using a titrated solutionof hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 71.19 5.36 8.48 6.69 %found 71.34 5.27 8.42 6.66

EXAMPLE 22(3aα,9bβ)-8-Cyano-2-[2-(4-biphenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith that of Preparation K. The product is converted into thecorresponding hydrochloride using a titrated solution of hydrochloricacid in ethanol.

Elemental microanalysis: C H Cl N % calculated 74.67 6.06 8.51 6.76 %found 74.90 6.04 8.50 6.72

EXAMPLE 23(3aα,9bβ)-8-Cyano-2-[2-(4-bromophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith that of Preparation L and without the addition of acetic acid. Theproduct is converted into the corresponding hydrochloride using atitrated solution of hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 56.90 4.82 8.19 6.40 %found 57.23 4.80 8.45 6.67

EXAMPLE 24(3aα,9bβ)-8-Cyano-2-[2-(4′-fluoro-4-biphenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 21, replacing the compound of Example 6 with thatof Example 23 in the form of its base.

Elemental microanalysis: C H Cl N % calculated 71.62 5.66 7.98 6.42 %found 71.79 5.56 8.15 6.44

EXAMPLE 25(3aα,9bβ)-8-Cyano-2-(4-phenyloxybenzyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 4-phenyloxybenzaldehyde. The product is converted into thecorresponding hydrochloride using a titrated solution of hydrochloricacid in ethanol

Elemental microanalysis: C H Cl N % calculated 71.46 5.58 8.58 6.77 %found 71.68 5.53 8.46 6.69

EXAMPLE 26(3aα,9bβ)-2-(4-Benzyloxybenzyl)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 4-benzyloxybenzaldehyde and without the addition of acetic acid.The product is converted into the corresponding hydrochloride using atitrated solution of hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 71.90 5.91 8.22 6.42 %found 72.13 5.82 8.19 6.47

EXAMPLE 27(3aα,9bβ)-8-Cyano-2-(2-furylmethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 2-furaldehyde and without the addition of acetic acid. The productis converted into the corresponding hydrochloride using a titratedsolution of hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 64.32 5.48 11.33 8.53 %found 64.46 5.41 11.19 8.84

EXAMPLE 28(3aα,9bβ)-2-(3-Bromobenzyl)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 3-bromobenzaldehyde and without the addition of acetic acid. Theproduct is converted into the corresponding hydrochloride using atitrated solution of hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 56.06 4.43 8.62 6.62 %found 56.25 4.47 8.74 6.90

EXAMPLE 29(3aα,9bβ)-2-(2-Bromobenzyl)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 2-bromobenzaldehyde and without the addition of acetic acid. Theproduct is converted into the corresponding hydrochloride using atitrated solution of hydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 55.95 4.48 8.46 6.61 %found 56.25 4.47 8.74 6.90

EXAMPLE 30(3aα,9bβ)-8-Cyano-2-[4-(2-thienyl)benzyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 21, replacing the 4-fluorophenylboronic acid with2-thienylboronic acid.

Elemental microanalysis: C H Cl N % calculated 67.83 5.21 8.25 6.83 %found 67.55 5.18 8.67 6.85

EXAMPLE 31(3aα,9bβ)-8-Cyano-2-{4-[2-(4-methoxyphenyl)vinyl]benzyl}-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

4 mmol of 4-methoxystyrene and then 3.9 ml of triethylamine are added to4 mmol of the compound of Example 6, in the form of its base, in 40 mlof DMF. 0.2 mmol of palladium diacetate and 0.8 mmol oftri-ortho-tolylphosphine are added to the reaction mixture. The mixtureis heated at 100° C. for 3 hours. After cooling and after the additionof water, the mixture is decanted. The aqueous phase is extracted twicewith 50 ml of ether each time. The organic phases are combined and driedover magnesium sulphate. The expected product is obtained afterpurification by chromatography on silica gel. The correspondinghydrochloride is obtained by the action of a titrated a solution ofhydrochloric acid in ethanol.

Elemental microanalysis: C H Cl N % calculated 72.90 6.00 7.41 6.14 %found 73.27 5.93 7.72 6.10

EXAMPLE 32(3aα,9bβ)-8-Cyano-2-{4-[2-(4-methoxyphenyl)ethyl]benzyl}-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

4 mmol of the compound of Example 31 are dissolved in 150 ml of ethanol.After the addition of 100 mg of palladium-on-carbon, the mixture isstirred under atmospheric hydrogen pressure. After 2 hours at roomtemperature, the reaction mixture is filtered and the filtrate is thenevaporated to yield the expected compound.

Elemental microanalysis: C H Cl N % calculated 72.82 6.39 7.81 6.01 %found 72.95 6.34 7.69 6.07

EXAMPLE 33(3aα,9bβ)-8-Cyano-2-{2-[4-(2-thienyl)phenyl]ethyl}-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 30, replacing the compound of Example 6 with thatof Example 23 in the form of its base.

Elemental microanalysis: C H Cl N % calculated 67.36 5.59 8.50 6.68 %found 67.22 5.64 8.62 6.81

EXAMPLE 34(3aα,9bβ)-8-Cyano-2-[2-(4-methylsulphonylaminophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, replacing the compound of Preparation A in Stepa with the compound described in Preparation M.

Elemental microanalysis: C H Cl N % calculated 58.12 5.57 8.17 9.68 %found 57,79 5,75 8,44 9,32

EXAMPLE 354-Bromo-N-{4-[(3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl]butyl}benzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation N.

EXAMPLE 36N-[4-((3aα,9bβ)-8-Cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)propyl]-4-fluorobenzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation O.

Elemental microanalysis: C H Cl N % calculated 62.92 5.67 8.45 9.80 %found 63.54 5.57 8.52 10.10

EXAMPLE 37 4-Acetyl-N-{4-[2-(8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)ethyl)phenyl]benzamide hydrochloride

Step a:(3aα,9bβ)-8-Cyano-2-[2-(4-nitrophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith that of Preparation M.

Step b:(3aα,9bβ)-8-Cyano-2-[2-(4-aminophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4]pyrrole

The expected product is obtained in accordance with the processdescribed in Example 3, Step b.

Step c:4-Acetyl-N-{4-[2-(8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]-pyrrol-2-yl)ethyl]phenyl}benzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step c, replacing the methanesulphonyl chloridewith the compound of Preparation P.

EXAMPLE 384-Cyano-1-methoxy-N-[4-(8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)butyl]-2-naphthylamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation Q.

Elemental microanalysis: C H Cl N % calculated 67.42 5.61 6.78 10.52 %found 67.37 5.65 6.86 10.84

EXAMPLE 394-Fluoro-N-[2-((3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)ethyl]benzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation R.

EXAMPLE 404-Phenyl-N-[2-((3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl)ethyl]benzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation S.

EXAMPLE 41N-{4-[(3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]-pyrrol-2-yl]butyl}-4-methoxybenzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation T.

EXAMPLE 42N-{4-[(3aα,9bβ)-8-Cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl]butyl}-4-nitrobenzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation U.

EXAMPLE 434-Bromo-N-{3-[(3aα,4bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl]propyl}benzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation V.

EXAMPLE 44N-{3-[(3aα,9bβ)-8-Cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl]propyl}-4-nitrobenzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation W.

EXAMPLE 454-Bromo-N-{2-[(3aα,9bβ)-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl]ethyl}benzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation X.

EXAMPLE 46N-{2-[(3aα,9bβ)-8-Cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrol-2-yl]ethyl}-4-methoxybenzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, replacing the product of Preparation D with thecompound described in Preparation Y.

EXAMPLE 47(3aα,9bβ)-8-Cyano-2-(2-pyridylmethyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 2-pyridylcarboxaldehyde.

EXAMPLE 48(3aα,9bβ)-2-[(6-[1,4]Benzodioxinyl)methyl]-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 6-formyl[1,4]benzodioxin.

EXAMPLE 49(3aα,9bβ)-2-[(5-Benzothienyl)methyl]-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, Step a, replacing the product of Preparation Awith 5-formylbenzothiophene.

EXAMPLE 50(3aα,9bβ)-8-Cyano-2-[2-(4-phenylsulphonylaminophenyl)ethyl]-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrolehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 3, replacing the methanesulphonyl chloride in Stepc with benzenesulphonyl chloride.

EXAMPLE 51(4aα,10bβ)-4-(4-Bromobenzyl)-9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 6, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno-[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 52(4aα,10bβ)-9-Cyano-4-[4-(4-fluorophenyl)benzyl]-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 21, using as starting material the product ofexample 51.

EXAMPLE 53(4aα,10bβ)-4-(4-Acetylaminobenzyl)-9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 7, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno-[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 54(4aα,10bβ)-4-[2-(4-Acetylaminophenyl)ethyl]-9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 4, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno-[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 55(4aα,10bβ)-9-Cyano-4-furylmethyl-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyridinehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 27, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 564-Bromo-N-[4-((4aα,10bβ)-9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyrid-4-yl)butyl]benzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 15, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 574-Cyano-N-[4-((4aα,10bβ)-9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyrid-4-yl)butyl]benzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 13, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 58N-[4-((4aα,10bβ)-9-Cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyrid-4-yl)butyl]-4-phenylbenzamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 14, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 594-Bromo-N-[4-((4aα,10bβ)-9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-b]pyrid-4-yl)butyl]benzenesulphonamidehydrochloride

The expected product is obtained in accordance with the processdescribed in Example 35, using as starting material9-cyano-1,3,4,4a,5,10b-hexahydro-2H-chromeno[3,4-c]pyridine (the latterhaving been prepared from the analogue hydroxylated in the 9 positiondescribed in J. Med. Chem., 1989, 32, 720).

EXAMPLE 60 In vitro Measurement of the Affinity to D₂ and D₃ Receptors

The affinity of the compounds of the invention to D₂ and D₃ receptors(expressed independently and in a stable manner in CHO cells) wasdetermined with membrane preparations using [¹²⁵I]-iodosulpiride asradioligand (Sokoloff et al., quoted reference). The results areexpressed as pKi.

The results demonstrate in vitro the selectivity of the compounds of theinvention for D₃ receptors compared with D₂ receptors. This is trueespecially of the compound of Example 4, for which the selectivity isgreater than log 1.5.

EXAMPLE 61 In vivo Demonstration of the Selectivity for D₃ ReceptorsCompared with D₂ Receptors

The in vivo selectivity of the compounds of the invention for D₃receptors compared with D₂ receptors was demonstrated in the rat by thecapacity of the compounds to modulate the hypothermia induced by the D₃dopaminergic agonist 7-OH-DPAT, control of the body temperature beingdependent on the post-synaptic D₃ receptor (M. Millan, quotedreference).

Method

The tests were carried out on male Wistar rats weighing 200-250 g placedin individual cages with free access to food and water. The productswere dissolved in distilled water to which several drops of lactic acidare added. The injections were carried out by the subcutaneous route.

In a first period the test product or the carrier is injected, then therats are put back in their cages for 30 minutes. In a second period therats are given an injection of 7-OH-DPAT or carrier and are placed backin their cages. Thirty minutes later, the rectal temperature is measured(using a digital thermistoprobe, Millan et al., J. Pharmacol. Exp.Ther., 1993, 264, 1364-76), and the difference in relation to basevalues is determined (ΔT° C.).

Results

The compounds of the invention appear to be capable of significantmodulation of the hypothermia induced by 7-OH-DPAT (in the case of themore active compounds, the effect of the reference D₃ ligand isvirtually nullified).

EXAMPLE 62 Pharmaceutical Composition

Formulation for the preparation of 1000 tablets each containing 10 mg ofactive ingredient

compound of Example 4 . . . 10 g

hydroxypropyl cellulose . . . 2 g

wheat starch . . . 10 g lactose . . . 100 g

magnesium stearate . . . 3 g talc . . . 3g

We claim:
 1. A method for treating a living body afflicted with acondition requiring a D₃ receptor ligand selected from depression,schizophrenia, psychoses, Parkinsons's disease, memory disorders, anddisorders associated with drug abuse, comprising the step ofadministering to the living body an amount of a compound selected fromthose of formula (VIII):

wherein: q represents 1, Z represents cyano or aminocarbonyl, R₇represents benzyl or acylamino-(C₁-C₆)-alkyl in which the alkyl moietyis linear or branched and in which the acyl group is benzoyl,naphthylcarbonyl, thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl orpyridinylcarbonyl, each of which is optionally substituted by one ormore halogen or trihalomethyl, alkoxy, or hydroxy, the junction betweenthe rings B and C is in the trans configuration, and their enantiomers,diastereoisomers and addition salts thereof with apharmaceutically-acceptable acid or base.
 2. A method for treating aliving body according to claim 1 wherein the compound administered isselected from(3aα,9bβ)-2-benzyl-8-cyano-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole,its enantiomers, and addition salts thereof with apharmaceutically-acceptable acid.
 3. A pharmaceutical composition usefulas a D₃ receptor ligand comprising as active principle an effectiveamount of a compound of Formula VIII as defined in claim 1, togetherwith one or more pharmaceutically-acceptable excipients or vehicles.